A simple eutectic composition consists of two compounds which are completely miscible in the liquid state but only to a very limited extent in the solid state. The unique property of a eutectic is that it has a lower melting temperature than that of either pure compound. Eutectics have many of the same properties as each phase, but behave differently from either component with respect to melting point, solubility and chemical stability.
A eutectic composition is clearly differentiated from the phenomenon of co-crystal formation. A person skilled in the art will appreciate that in a eutectic composition the two constituent materials are independently crystalline whereas in the case of a co-crystal a completely new crystalline phase forms and in effect replaces the separate crystalline phases with respect to the component molecules within each unit cell. Thus in a co-crystal molecules of both substances are present within the unit cell in an ordered manner.
Solid eutectic compositions may be prepared by rapid cooling of a co-melt of two compounds in order to obtain a physical mixture of very fine crystals of the two components. The preparation of eutectic compositions is a way for formulating drugs which are poorly soluble in gastrointestinal fluids. The active ingredient is mixed with a highly soluble carrier at such proportions that the composition obtained dissolves more easily than the single solid components due to the microcrystalline properties of the combination. This is described in: A. Florence, T. Attwood, Physicochemical Principles of Pharmacy, 4th Ed, Pharmaceutical Press 2006, p. 28.
When the eutectic composition is exposed to the gastrointestinal fluids, the soluble carrier dissolves rapidly, leaving the insoluble drug in an extremely fine state of subdivision. The large surface area of the resulting suspension should result in an enhanced dissolution rate and, consequently, improved bioavailability.
Eutectic compositions are known in the field of local anaesthetics. For example, U.S. Pat. No. 5,993,836 describes a local, topical, transdermal aesthetic formulation comprising a eutectic composition of lidocaine and prilocaine in a defined weight ratio in a lipophilic base. In this eutectic composition, both anaesthetics remain liquid at room temperature and therefore the penetration and absorption of the anaesthetics through the skin is enhanced over applying each anaesthetic separately in crystalline form.
WO 1998/51283 discloses the use of topical pharmaceutical compositions formed by incorporating, in a suitable delivery system, a eutectic composition of at least two pharmacologically active agents, which may be structurally and/or pharmacologically diverse. These compositions achieve enhanced topical permeation for each of the pharmacologically active agents by means of improved drug release from the topical composition itself and not by interaction with the skin. Preferred compositions are those in which the agents possess complementary but different pharmacological activities.
US 2008/0020008 discloses a method of making a eutectic crystalline sugar alcohol designed for improved flavours and taste sensation.
To the best of the inventors' knowledge there is no disclosure of using eutectic compositions in the treatment of respiratory diseases. Further, there is no disclosure of using eutectic compositions in pressurized metered dose inhalers, dry powder inhalers or breath activated nasal inhalers. Further, there is no disclosure of using eutectic compositions which are inhaled into the lung.
Inhalation represents a very attractive, rapid and patient-friendly route for the delivery of systemically acting drugs, as well as for drugs that are designed to act locally on the lungs themselves, such as to treat respiratory diseases, preferably infection or chronic respiratory diseases for example asthma, chronic obstructive pulmonary disease and cystic fibrosis. Not only is it particularly desirable and advantageous to develop technologies for delivering drugs to the lungs in a predictable and reproducible manner but it is important that for concurrent delivery of two or more drugs to the lung the solid-state chemistry of all constituent and mechanically blended mixtures thereof is well understood.
Powder technology, however, for successful dry powders products remains a significant technical hurdle. Formulations must have suitable flow properties, not only to assist in the manufacture and metering of the powders, but also to provide reliable and predictable re-suspension and fluidisation, and to avoid excessive retention of the powder within the dispensing device. The drug particles or particles of pharmacologically active ingredients in the re-suspended powder must aerosolise appropriately so that they can be transported to the appropriate target area within the lung. Typically, for lung deposition, the active particles have a diameter of less than 10 μm, frequently 0.1 to 7 μm or 0.1 to 5 μm.
In this kind of system the interaction between drug-to-drug and drug-to-carrier particles and particle-to-wall are of great importance for successful drug delivery to the deep lung. Turning to drug-to-drug interaction the interaction between particles is determined by adhesion and cohesion forces such as van der Waals, capillary, and coulombic forces. The strength of these forces is affected by the particle size, contact surface area and morphology.
Fine particles 10 μm and smaller, tend to be increasingly thermodynamically unstable as their surface area to volume ratio increases, which provides an increasing surface free energy with this decreasing particle size, and consequently increases the tendency of particles to agglomerate and the strength of the agglomerate. The present invention is concerned with the interaction between particles of different crystalline components.
An additional problem is the variability in surface properties of drug particles. Each pharmacologically active agent powder has its own unique inherent stickiness or surface energy, which can range tremendously from compound to compound. Further, the nature of the surface energies can change for a given compound depending upon how it is processed. For example, high shear blending can lead to significant variations in surface properties because of the aggressive nature of the collisions it employs. Such variations can lead to increased surface energy and increased cohesiveness and adhesiveness. Even in highly regular, crystalline powders, the short range Lifshitz-van der Waals forces can lead to highly cohesive and adhesive powders.
The blended micronized drug particles are loosely agglomerated via Lifshitz-van der Waals forces only. It is important for the function of such a formulation that no capillary forces are formed, because the particle agglomerates must be de-agglomerated in the air stream. Capillary forces are usually several times larger than, for example, Lifshitz-van der Waals forces, and the ability of such an agglomerate to be split into the single particles decreases with increasing autoadhesion forces holding the agglomerates together.
Two common techniques to produce fine particles for dry particle inhalers (DPIs) are mechanical micronization and spray drying. A high-energy milling operation generates particles that are highly charged and thus very cohesive and adhesive if blended with different micronized powders. The produced particles often contain irregular fragments that can form strong aggregates. In addition, multistep processing may cause significant losses of materials during powder production and variability of the product properties from batch to batch. Unlike milling, the spray-drying technique is a one-step continuous process that can directly produce pharmaceutical particles with a desired size. No surfactants or other solubilizing agents are needed in the process. However, the thermal history and drying rate of each particle is difficult to control due to the high flow rates needed in the process and limited controllable parameters. Consequently, the produced particles are usually amorphous and thus sensitive to temperature and humidity variations that may cause structural changes and sintering of the particles during storage of the powder.
It is known to deliver two pharmacologically active ingredients to the lung simultaneously. For example, Advair and Symbicort co-deliver a bronchodilator and a corticosteroid, and therapeutics are known whereby an anticholinergic, such as glycopyrronium bromide, and a bronchodilator, such as indacaterol are administered together. There is a need however, to improve the efficacy of the pharmacologically active ingredients. Further there is a need to improve the delivery of both the pharmacologically active ingredients to the same area in the lung, or the whole of the area of the lung by co-delivery and co-location of the drug within the lung. Further, there is a need to improve the onset time of the pharmacologically active ingredients. Further, there is a need to improve the rate of dissolution of the pharmacologically active ingredient upon deposition as a dry powder within the lung bronchia and alveoli.